4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway.
Growth factors and hormones activate protein translation by phosphorylation and inactivation of the translational repressors, the eIF4E-binding proteins (4E-BPs), through a wortmannin- and rapamycin-sensitive signaling pathway. The mechanism by which signals emanating from extracellular signals lead to phosphorylation of 4E-BPs is not well understood. Here we demonstrate that the activity of the serine/threonine kinase Akt/PKB is required in a signaling cascade that leads to phosphorylation and inactivation of 4E-BP1. PI 3-kinase elicits the phosphorylation of 4E-BP1 in a wortmannin- and rapamycin-sensitive manner, whereas activated Akt-mediated phosphorylation of 4E-BP1 is wortmannin resistant but rapamycin sensitive. A dominant negative mutant of Akt blocks insulin-mediated phosphorylation of 4E-BP1, indicating that Akt is required for the in vivo phosphorylation of 4E-BP1. Importantly, an activated Akt induces phosphorylation of 4E-BP1 on the same sites that are phosphorylated upon serum stimulation. Similar to what has been observed with serum and growth factors, phosphorylation of 4E-BP1 by Akt inhibits the interaction between 4E-BP1 and eIF-4E. Furthermore, phosphorylation of 4E-BP1 by Akt requires the activity of FRAP/mTOR. FRAP/mTOR may lie downstream of Akt in this signaling cascade. These results demonstrate that the PI 3-kinase-Akt signaling pathway, in concert with FRAP/mTOR, induces the phosphorylation of 4E-BP1.
Gingras
A C
AC
Department of Biochemistry, McGill University Montreal, Quebec, Canada H3G 1Y6.
Kennedy
S G
SG
O'Leary
M A
MA
Sonenberg
N
N
Hay
N
N
D048868:Adaptor Proteins, Signal Transducing; D000730:Androstadienes / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D004351:Drug Resistance; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D010448:Peptide Initiation Factors / Q000378:metabolism; D010449:Peptide Mapping; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010748:Phosphopeptides / Q000302:isolation & purification; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D011090:Polyenes / Q000494:pharmacology; D014176:Protein Biosynthesis; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin
D048868:Adaptor Proteins, Signal Transducing; D000730:Androstadienes; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; D010448:Peptide Initiation Factors; D019869:Phosphatidylinositol 3-Kinases; D010748:Phosphopeptides; D010750:Phosphoproteins; D017853:Phosphotransferases (Alcohol Group Acceptor); D011090:Polyenes; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D000077191:Wortmannin; C087000:EIF4EBP1 protein, human; C104151:EIF4EBP2 protein, human; C546842:MTOR protein, human; C494918:AKT1 protein, human